Targeting DJ-1 for cardioprotection
Authors: S Hernandez Resendiz, S Lu, A Prakash, GE Crespo-Avilan, DJ Hausenloy
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The National Medical Research Council (NMRC) Background Additional protection beyond timely reperfusion is still needed as more patients who have survived an acute myocardial infarction (AMI) developed heart failure (HF)1. DJ-1 was recently reported as a cytoprotective protein that preserves mitochondrial complex I activity and subsequently inhibits mitochondrial reactive species (ROS) production2. DJ-1 downregulation dramatically increases the susceptibility to cell death after myocardial infarction in mice. A substantial reduction in total DJ-1 protein levels in left ventricular tissue has been identified in patients at the end-stage of human HF3, suggesting that DJ-1 protects the myocardium against AMI cell death and is essential in the remodelling process post-infarct. Purpose: The translation of cardioprotection to clinical practice has been difficult, and it remains a challenge between the bench and the bedside. Nanotechnology has shown significant improvements in the settings of AMI. Given the protective effect observed with DJ-1, we designed ND-13, a new cell-permeable 13- fragment of the DJ-1 amino acid sequence. Then, we loaded it into nanoparticles (ND-13NPs) to achieve cardioprotective outcomes against IRI. Methods: We tested the efficacy and efficiency of our new ND-13NPs to reduce infarct size in the ex vivo heart perfused IRI model and the in vivo AMI-murine model. Results: Naked ND-13 (20µM) continuously perfused for the first 15 minutes of reperfusion significantly improved LV pressure and systolic function. Afterwards, we tested 60 mg/Kg of the naked peptide injected 5 minutes before reperfusion in the in vivo model. ND-13 reduced 35% of the infarct size (non-treated, 49 ± 6.4% vs. treated, 32 ± 5 %). Fluorescently loaded ND-13NPs were intravenously injected into infarcted mice to assess their distribution in cardiac tissue. The ND-13NPs were abundantly detected in the infarct border and minimally detected in the remote myocardium. 20mg/Kg of ND-13 loaded into NPs reduced 45% the infarct size compared with 60mg/Kg and 20mg/Kg of naked ND-13 (27 ± 6% vs. 32 ± 5% and 44 ± 8%, respectively). We demonstrated that NPs improved the delivery and efficacy of ND-13 in the ischemic heart following AMI. We observed a robust antioxidative effect when the infarcted heart was treated with ND-13NPs (90 ± 1.5% vs 39 ± 9%, respectively). The activation of the myocardial reperfusion injury salvage kinase (RISK) and the survivor activating factor enhancement (SAFE) pathway at reperfusion protects the mitochondria against IRI. Therefore, we addressed whether ND-13NPs impact mitochondrial function. Can ND-13 protect beyond a cardioprotective pathway, or has the threshold of protection already been achieved by activating a direct effect on mitochondria? Conclusion: Intravenously injected ND-13NPs selectively accumulated in the infarct area and protects the myocardium from IRI via the ROS-mitochondria effect. This new drug may potentially bridge the gaps between basic and clinical research.